This invention relates generally to N-(amidinophenyl)cyclourea analogs which are inhibitors of factor Xa, pharmaceutical compositions containing the same, and methods of using the same as anticoagulant agents for treatment and prevention of thromboembolic disorders.
Bovy et al, U.S. Pat. No. 5,430,043 describe phenyl amidines of the formula: 
which are reported to be platelet aggregation inhibitors. However, no mention is made of inhibiting Factor Xa.
Himmelsbach et al, CA 2,105,934, address cyclic ureas of the formula: 
wherein, among the multitude of choices, X may be a carbonyl, Y may be an C2-4 alkylene, Ra may be Axe2x80x94Bxe2x80x94Cxe2x80x94 and Rb may be xe2x80x94Dxe2x80x94Exe2x80x94F. Group F is selected from xe2x80x94CO2R, phosphono, tetrazolyl, and R8COxe2x80x94Oxe2x80x94CHR9xe2x80x94Oxe2x80x94COxe2x80x94. The compounds described by the above formula are alleged to have aggregation inhibiting and/or fibrinogen binding properties. Factor Xa inhibiting is not discussed.
Lam et al, WO 94/19329, report cyclic carbonyls which may be cyclic ureas of the formula: 
wherein at least one of R4, R4a, R7, and R7a is other than hydrogen. Compounds of this sort are said to be useful as HIV protease inhibitors. N-(Amidinophenyl)cycloureas are not suggested as factor Xa inhibitors.
Currie et al, WO 96/36639, set forth amidine derivatives of the formula: 
wherein A may be a 6-membered cyclic urea, which may be useful as anti-platelet aggregation inhibitors. However, Y is nitrate, nitrite, or a nitric oxide donating group. The present compounds, in contrast, do not contain the nitric oxide donating groups of WO 96/36639.
Klinger et al, WO 94/21607, illustrate heterocyclic compounds of the formula: 
wherein, upon judicious selection of variables, Z1 may be a carbonyl, A may be NR1, R1 may be an amidino-substituted phenyl, and B and Z2 may each be CH2. However, the present compounds do not include the right-side chain shown above. Mohan et al, WO 96/38421, describe N,N-di(arylmethyl)cyclic urea derivatives of the formula: 
wherein R7 and R8 may combine to form a benzene ring and the double bond shown may be absent, which may be useful as Factor Xa inhibitors. These compounds are preferably bis-amidino substituted. However, the presently claimed compounds are neither bis-benzyl nor bis-amidino substituted.
Chakravarty et al, WO 95/03044, discuss benzimidazoles substituted with phenoxyphenylacetic acid dervatives of the formula: 
wherein R12 may be a substituted aryl group. But, this reference does not consider amidino-phenyl groups. Furthermore, the present compounds do not contain the above variable Z, which is defined as a carbonyl, sulfonyl, or phosphoryl group.
Activated factor Xa, whose major practical role is the generation of thrombin by the limited proteolysis of prothrombin, holds a central position that links the intrinsic and extrinsic activation mechanisms in the final common pathway of blood coagulation. The generation of thrombin, the final serine protease in the pathway to generate a fibrin clot, from its precursor is amplified by formation of prothrombinase complex (factor Xa, factor V, Ca2+ and phospholipid). Since it is calculated that one molecule of factor Xa can generate 138 molecules of thrombin (Elodi, S., Varadi, K.: Optimization of conditions for the catalytic effect of the factor IXa-factor VIII Complex: Probable role of the complex in the amplification of blood coagulation. Thromb. Res. 1979, 15, 617-629), inhibition of factor Xa may be more efficient that inactivation of thrombin in interrupting the blood coagulation system.
Therefore, efficacious and specific inhibitors of factor Xa are needed as potentially valuable therapeutic agents for the treatment of thromboembolic disorders. It is thus desirable to discover new factor Xa inhibitors.
Accordingly, one object of the present invention is to provide novel N-(amidinophenyl)cyclourea factor Xa inhibitors or pharmaceutically acceptable salts or prodrugs thereof.
It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
It is another object of the present invention to provide a method for treating thromboembolic disorders comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors"" discovery that compounds of formula (I): 
or pharmaceutically acceptable salt or prodrug forms thereof, wherein A, B, R1, R2, m and n are defined below, are effective factor Xa inhibitors.
[1] Thus, in a first embodiment, the present invention provides novel compounds of formula I: 
or stereoisomers or pharmaceutically acceptable salt forms thereof, wherein;
one of D and Dxe2x80x2 is selected from CN, C(xe2x95x90NR11)NR12R13, NHC(xe2x95x90NR11)NR12R13, NR12CH(xe2x95x90NR11), C(O)NR12R13, and (CH2)tNR12R13 and the other is H;
R1 is selected from H, (CH2)rOR3, halo, C1-4 alkyl, (CH2)rNR4R4xe2x80x2, (CH2)rCO2H, (CH2)rC(xe2x95x90O)R4, (CH2)rNR4C(xe2x95x90O)R4, (CH2)rSO2R5, and (CH2)rNR4SO2R5;
R2 is selected from H, xe2x95x90O, C1-4 alkyl substituted with 0, 1, or 2 R7, C2-6 alkenyl substituted with 0, 1, or 2 R7, (CH2)rOR3, (CH2)rC(O)R4, (CH2)rOC(O)R4, (CH2)rNR3R3xe2x80x2, (CH2)rNR3C(O)R4, (CH2)rSO2R5, (CH2)rNR3SO2R5, C3-10 carbocyclic residue substituted with 0-2 R6; and, 5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R6;
R2a is absent;
alternatively, R2 and R2a may be present on adjacent carbon atoms and combine to form a benzene ring substituted with 0-2 R10 or a 5-6 membered aromatic heterocycle containing 0-2 heteratoms selected from the group consisting of N, O, and S and substituted with 0-2 R10a;
R3 and R3xe2x80x2 are independently selected from H, C1-4 alkyl, benzyl and phenyl;
R3 and R3xe2x80x2 may be taken together to form a 5 or 6 membered ring substituted with 0-2 R6;
R4 and R4xe2x80x2 are independently selected from H, OR3, C1-4 alkyl, phenyl and NR3R3xe2x80x2;
R5 is selected from C1-4 alkyl, phenyl and NR3R3xe2x80x2;
Z is selected from a bond, C1-4 alkylene, (CH2)rO(CH2)r, (CH2)2NR3(CH2)r, (CH2)rC(O)(CH2)r, (CH2)rC(O)O(CH2)r, (CH2)2OC(O)(CH2)r, (CH2)rC(O)NR3(CH2)r, (CH2)2NR3C(O)(CH2)r, (CH2)2OC(O)O(CH2)r, (CH2)2OC(O)NR3(CH2)r, (CH2)2NR3C(O)O(CH2)r, (CH2)2NR3C(O)NR3(CH2)r, (CH2)rS(O)p(CH2)r, (CH2)rSO2NR3(CH2)r, (CH2)2NR3SO2(CH2)r, and (CH2)2NR3SO2NR3(CH2)r;
A is selected from:
C3-10 carbocyclic residue substituted with 0-2 R6, and 5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R6;
B is selected from:
Xxe2x80x94Y, NR3R3xe2x80x2, C(O)NR3R3xe2x80x2, SO2NR3R3xe2x80x2,
benzyl substituted with 0-2 R6,
C3-10 carbocyclic residue substituted with 0-2 R6, and
5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R6;
X is selected from C1-4 alkylene, xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)CR3R3xe2x80x2xe2x80x94, xe2x80x94CR3R3xe2x80x2C(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94C(O)OCR3R3xe2x80x2xe2x80x94, xe2x80x94CR3R3xe2x80x2C(O)Oxe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94OC(O)CR3R3xe2x80x2xe2x80x94, xe2x80x94CR3R3xe2x80x2OC(O)xe2x80x94, xe2x80x94S(O)pxe2x80x94, xe2x80x94S(O)pCR3R3xe2x80x2xe2x80x94, xe2x80x94CR3R3xe2x80x2S(O)pxe2x80x94, xe2x80x94S(O)2NR3xe2x80x94, xe2x80x94NR3S(O)2xe2x80x94, xe2x80x94NR3S(O)2CR3R3xe2x80x2, xe2x80x94CR3R3xe2x80x2S(O)2NR3xe2x80x94, xe2x80x94NR3S(O)2NR3xe2x80x94, xe2x80x94C(O)NR3xe2x80x94, xe2x80x94NR3C(O)xe2x80x94, xe2x80x94C(O)NR3CR3R3xe2x80x2xe2x80x94, xe2x80x94NR3C(O)CR3R3xe2x80x2xe2x80x94, xe2x80x94CR3R3xe2x80x2C(O)NR3xe2x80x94, xe2x80x94CR3R3xe2x80x2NR3C(O)xe2x80x94, xe2x80x94NR3C(O)Oxe2x80x94, xe2x80x94OC(O)NR3xe2x80x94, xe2x80x94NR3C(O)NR3xe2x80x94, xe2x80x94NR3xe2x80x94, xe2x80x94NR3CR3R3xe2x80x2xe2x80x94, xe2x80x94CR3R3xe2x80x2NR3xe2x80x94, O, xe2x80x94CR3R3xe2x80x2Oxe2x80x94, xe2x80x94OCR3R3xe2x80x2xe2x80x94, S, xe2x80x94CR3R3xe2x80x2Sxe2x80x94, and xe2x80x94SCR3R3xe2x80x2xe2x80x94;
Y is selected from:
C1-4 alkyl substituted with 0-2 R6 
C3-10 carbocyclic residue substituted with 0-2 R6, and
5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R6;
R6 is selected from H, OH, CF3, (CH2)nOR3, halo, C1-4 alkyl, CN, NO2, (CH2)rNR3R3xe2x80x2(CH2)rC(O)R3, NR3C(O)R3xe2x80x2, NR3C(O)NR3R3xe2x80x2, SO2NR3R3xe2x80x2, NR3SO2NR3R3xe2x80x2, NR3SO2xe2x80x94C1-4 alkyl, SO2-phenyl, and NR3SO2R8;
R7 is selected from:
C3-10 carbocyclic residue substituted with 0-2 R6; and,
5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R6;
R8 is selected from:
C3-10 carbocyclic residue substituted with 0-2 R9; and,
5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R9;
R9 is selected from H, OH, (CH2)nOR3, halo, C1-4 alkyl, CN, NO2, (CH2)rNR3R3xe2x80x2, (CH2)rC(O)R3, NR3C(O)R3xe2x80x2, NR3C(O)NR3R3xe2x80x2, SO2NR3R3xe2x80x2, NR3SO2NR3R3xe2x80x2, and NR3SO2xe2x80x94C1-4 alkyl;
R10 is selected from H, OR3, halo, C1-4 alkyl, CN, NO2, NR3R3xe2x80x2, NR3C(O)R3xe2x80x2, NR3C(O)OR3xe2x80x2, NR3SO2-phenyl, and NR3SO2xe2x80x94C1-4 alkyl;
R10a if a substituent on nitrogen is selected from H and C1-4 alkyl;
R10a if a substituent on carbon is selected from H, C1-4 alkyl, NR3R3xe2x80x2, NR3C(O)R3xe2x80x2, NR3C(O)OR3xe2x80x2, NR3SO2-phenyl, and NR3SO2xe2x80x94C1-4 alkyl;
R11 is selected from H, OH, C1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkoxy, C1-4 alkoxycarbonyl, C6-10 aryloxy, C6-10 aryloxycarbonyl, C6-10 arylmethylcarbonyl, C1-4 alkylcarbonyloxy C1-4 alkoxycarbonyl, C6-10 arylcarbonyloxy C1-4 alkoxycarbonyl, C1-6 alkylaminocarbonyl, phenylaminocarbonyl, and phenyl C1-4 alkoxycarbonyl;
R12 is selected from H, C1-6 alkyl and (CH2)n-phenyl;
R13 is selected from H, C1-6 alkyl and (CH2)n-phenyl;
n is selected from 0, 1, 2, and 3;
m is selected from 0 and 1;
p is selected from 0, 1, and 2;
q is selected from 1, 2, 3, 4, and 5; and,
r is selected from 0, 1, and 2.
[2] In a preferred embodiment, the present invention provides compounds of formula I wherein:
is C(xe2x95x90NH)NH2;
Dxe2x80x2 is H;
R1 is selected from H, (CH2)rOR3, halo, (CH2)rNR4R4xe2x80x2, (CH2)rCO2H, (CH2)rC(xe2x95x90O)R4, (CH2)rNR4C(xe2x95x90O)R4, (CH2)rSO2R5, and (CH2)rNHSO2R5;
R2 is selected from H, xe2x95x90O, (CH2)rOR3, (CH2)rC(O)R4, (CH2)rOC(O)R4, (CH2)rNR3R3xe2x80x2, (CH2)rNR3C(O)R4, (CH2)rSO2R5, (CH2)rNR3SO2R5, C3-10 carbocyclic residue substituted with 0-2 R6; and, 5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R6;
R4 and R4xe2x80x2 are independently selected from H, OR3, C1-4 alkyl, and NR3R3xe2x80x2;
R5 is selected from C1-4 alkyl and NR3R3xe2x80x2;
Z is selected from a bond, C1-4 alkylene, (CH2)rC(O)(CH2)r, (CH2)rC(O)NR3(CH2)r, (CH2)2NR3C(O)(CH2)r, (CH2)2OC(O)NR3(CH2)r, (CH2)2NR3C(O)O(CH2)r, (CH2)2NR3C(O)NR3(CH2)r, (CH2)rS(O)p(CH2)r, (CH2)rSO2NR3(CH2)r, (CH2)2NR3SO2(CH2)r, and (CH2)2NR3SO2NR3(CH2)r; and,
X is selected from C1-4 alkylene, xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)CR3R3xe2x80x2xe2x80x94, xe2x80x94CR3R3xe2x80x2C(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94C(O)OCR3R3xe2x80x2xe2x80x94, xe2x80x94CR3R3xe2x80x2C(O)Oxe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94OC(O)CR3R3xe2x80x2xe2x80x94, xe2x80x94CR3R3xe2x80x2OC(O)xe2x80x94, xe2x80x94S(O)pxe2x80x94, xe2x80x94S(O)pCR3R3xe2x80x2xe2x80x94, xe2x80x94CR3R3xe2x80x2S(O)pxe2x80x94, xe2x80x94S(O)2NR3xe2x80x94, xe2x80x94C(O)NR3xe2x80x94, xe2x80x94NR3C(O)xe2x80x94, xe2x80x94NR3C(O)Oxe2x80x94, xe2x80x94OC(O)NR3xe2x80x94, xe2x80x94NR3C(O)NR3xe2x80x94, xe2x80x94NR3xe2x80x94, xe2x80x94NR3CR3R3xe2x80x2xe2x80x94, xe2x80x94CR3R3xe2x80x2NR3xe2x80x94, O, xe2x80x94CR3R3xe2x80x2O, and xe2x80x94OCR3R3xe2x80x2xe2x80x94,
[3] In a more preferred embodiment, the present invention provides compounds of formula I wherein:
R1 is selected from H, OR3, (CH2)OR3, halo, NR4R4xe2x80x2, (CH2)NR4R4xe2x80x2, C(xe2x95x90O)R4, (CH2)C(xe2x95x90O)R4, NHC(xe2x95x90O)R4, (CH2)NHC(xe2x95x90O)R4, SO2R5, (CH2)SO2R5, NHSO2R5, and (CH2) NHSO2R5;
R2 is selected from H, xe2x95x90O, OR3, C(O)R4, (CH2)C(O)R4, OC(O)R4, NR4R4xe2x80x2, NR3C(O)R4, and NR4SO2R5;
A is selected from:
C5-6 carbocyclic residue substituted with 0-1 R6, and
5-6 membered heterocyclic system containing from 1-2 heteroatoms selected from the group consisting of N and O substituted with 0-1 R6;
B is selected from: Y, Xxe2x80x94Y, and NR2R2a;
Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R4a;
phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazole, thiadiazole, triazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, benzofuran, benzothiofuran, indole, benzoxazole, benzthiazole, indazole, benzisoxazole, benzisothiazole, isoindazole, and benzothiadiazole;
Y may also be selected from the following bicyclic heteroaryl ring systems: 
K is selected from O, S, NH, and N;
X is selected from xe2x80x94CH2xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)CHR3xe2x80x94, xe2x80x94CHR3C(O)xe2x80x94, xe2x80x94S(O)pxe2x80x94, xe2x80x94S(O)pCR3R3xe2x80x2xe2x80x94, xe2x80x94CHR3S(O)pxe2x80x94, xe2x80x94S(O)2NR3xe2x80x94, xe2x80x94C(O)NR3xe2x80x94, xe2x80x94NR3C(O)xe2x80x94, xe2x80x94NR3xe2x80x94, xe2x80x94NR3CHR3xe2x80x94, and xe2x80x94CHR3NR3;
R6 is selected from H, OH, CF3, (CH2)nOR3, halo, C1-4 alkyl, CN, NO2, (CH2)rNR3R3xe2x80x2,(CH2)rC(O)R3, NR3C(O)R3xe2x80x2, SO2NR3R3xe2x80x2, SO2-phenyl, NR3SO2xe2x80x94C1-4 alkyl, and NR3SO2R8;
R8 is selected from:
C5-6 carbocyclic residue substituted with 0-2 R9; and,
5-6 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R9;
R9 is selected from H, OH, (CH2)nOR3, halo, C1-4 alkyl, CN, NO2, (CH2)rNR3R3xe2x80x2, (CH2)rC(O)R3, NR3C(O)R3xe2x80x2, NR3C(O)NR3R3xe2x80x2, SO2NR3R3xe2x80x2, NR3SO2NR3R3xe2x80x2, and NR3SO2xe2x80x94C1-4 alkyl; and,
p is 2.
[4] In an even more preferred embodiment, the present invention provides compounds of formula I wherein:
Z is selected from a bond, C1-4 alkylene, (CH2)rC(O)(CH2)r, (CH2)rC(O)NR3(CH2)r, (CH2)2NR3C(O)(CH2)r, (CH2)2NR3C(O)NR3(CH2)r, and (CH2)rS(CH2)r;
X is selected from xe2x80x94CH2xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)CHR3xe2x80x94, xe2x80x94CHR3C(O)xe2x80x94, xe2x80x94S(O)pxe2x80x94, xe2x80x94S(O)pCR3R3xe2x80x2xe2x80x94, xe2x80x94CHR3S(O)pxe2x80x94, xe2x80x94S(O)2NR3xe2x80x94, xe2x80x94C(O)NR3xe2x80x94, and xe2x80x94NR3C(O)xe2x80x94;
R6 is selected from H, OH, CF3, (CH2)nOR3, halo, C1-4 alkyl, CN, NO2, (CH2)rNR3R3xe2x80x2(CH2)rC(O)R3, NR3C(O)R3xe2x80x2, SO2NR3R3xe2x80x2, SO2-phenyl, and NR3SO2xe2x80x94C1-4 alkyl;
m is 1; and,
r is selected from 0 and 1.
[5] In a further preferred embodiment, the present invention provides compounds of formula I wherein:
R3 and R3xe2x80x2 are independently selected from H and C1-4 alkyl;
Z is selected from a bond, C1-4 alkylene, (CH2)rC(O)NR3(CH2)r, (CH2)2NR3C(O)(CH2)r, and (CH2)2NR3C(O)NR3(CH2)r;
A is selected from phenyl substituted with 0-1 R6 and a 6 membered heterocyclic system containing 1 N and 0-1 O atoms and substituted with 0-1 R6;
X is selected from xe2x80x94CH2xe2x80x94, xe2x80x94S(O)pxe2x80x94, xe2x80x94S(O)pCR3R3xe2x80x2xe2x80x94, xe2x80x94S(O)2NR3xe2x80x94, xe2x80x94C(O)NR3xe2x80x94, and;
Y is selected from phenyl, i-propyl, quinolynyl, thiadizolyl, benzothiadiazolyl, thiophenyl, pyridyl, cyclohexyl, and naphthyl, each of which is substituted with 0-2 R6; and,
n is selected from 0, 1, and 2.
[6] In an even further preferred embodiment, the present invention provides compounds of formula I wherein:
R3 and R3xe2x80x2 are independently selected from H and methyl;
Z is selected from a bond, CH2, xe2x80x94CH2CH2xe2x80x94, xe2x80x94CH2CH2CH2xe2x80x94 and xe2x80x94CH2CH2CH2CH2xe2x80x94;
A is selected from phenyl substituted with 0-1 R6, and piperidinyl substituted with 0-1 R6; and,
n is 2.
[7] In a particularly preferred embodiment, the present invention provides compounds selected from:
N-(3-amidinophenyl)-Nxe2x80x2-((4-((2-sulphonamido)phenyl)phenyl)methyl)cycloheptylurea;
N-(3-amidinophenyl)-Nxe2x80x2-(1-benzylpiperidin-4-yl)cycloheptylurea;
N-(3-amidinophenyl)-Nxe2x80x2-(1-(picolin-2-yl)piperidin-4-yl)cycloheptylurea;
N-(3-amidinophenyl)-Nxe2x80x2-(1-(picolin-3-yl)piperidin-4-yl)cycloheptylurea;
N-(3-amidinophenyl)-Nxe2x80x2-(1-(picolin-4-yl)piperidin-4-yl)cycloheptylurea;
N-(3-amidinophenyl)-Nxe2x80x2-(1-(a-phenethyl)piperidin-4-yl)cycloheptylurea;
N-(3-amidinophenyl)-Nxe2x80x2-(1-((phenyl)methane)sulfonyl)-piperidin-4-yl)cycloheptylurea;
N-(3-amidinophenyl)-Nxe2x80x2-(1-(phenyl)sulfonylpiperidin-4-yl)cycloheptylurea;
N-(3-amidinophenyl)-Nxe2x80x2-(1-(quinolin-8-yl)sulfonylpiperidin-4-yl)cycloheptylurea;
N-(3-amidinophenyl)-Nxe2x80x2-(1-(2-fluorophenyl)sulfonylpiperidin-4-yl)cycloheptylurea;
N-(3-amidinophenyl)-Nxe2x80x2-(1-(4-acetamidophenyl)sulfonyl-piperidin-4-yl)cycloheptylurea;
N-(3-amidinophenyl)-Nxe2x80x2-(1-(2-aminophenyl)sulfonylpiperidin-4-yl)cycloheptylurea;
N-(3-amidinophenyl)-Nxe2x80x2-(1-(3-aminophenyl)sulfonylpiperidin-4-yl)cycloheptylurea;
N-(3-amidinophenyl)-Nxe2x80x2-(1-(4-aminophenyl)sulfonylpiperidin-4-yl)cycloheptylurea;
N-(3-amidinophenyl)-Nxe2x80x2-(1-((2-aminophenyl)methane)sulfonyl)-piperidin-4-yl)cycloheptylurea;
N-(3-amidinophenyl)-Nxe2x80x2-(1-((2-acetamido-phenyl)methane)-sulfonylpiperidin-4-yl)cycloheptylurea;
N-(3-amidinophenyl)-Nxe2x80x2-(1-((thiophen-2-yl)sulfonyl)piperidin-4-yl)cycloheptylurea;
N-(3-amidinophenyl)-Nxe2x80x2-(1-((5-chlorothiophen-2-yl)sulfonyl)-piperidin-4-yl)cycloheptylurea;
N-(3-amidinophenyl)-Nxe2x80x2-(1-((5-carbomethoxythiophen-2-yl)sulfonyl)piperidin-4-yl)cycloheptylurea;
N-(3-amidinophenyl)-Nxe2x80x2-(1-((benzo-2,1,3-thiadiazo-4-yl)sulfonyl)piperidin-4-yl)cycloheptylurea;
N-(3-amidinophenyl)-Nxe2x80x2-(1-((cyclohexyl)sulfamido)piperidin-4-yl)cycloheptylurea;
N-(3-amidinophenyl)-Nxe2x80x2-(1-((isopropyl)sulfamido)piperidin-4-yl)cycloheptylurea;
N-(3-amidinophenyl)-Nxe2x80x2-(1-((phenyl)sulfamido)piperidin-4-yl)cycloheptylurea;
N-(3-amidinophenyl)-Nxe2x80x2-(1-((isopropyl)sulfonyl)piperidin-4-yl)cycloheptylurea;
N-(3-amidinophenyl)-Nxe2x80x2-(1-((5-amino-4-methylthiazol-2-yl)sulfonyl)piperidin-4-yl)cycloheptylurea;
N-(3-amidinophenyl)-Nxe2x80x2-(1-((5-acetamido-4-methylthiazol-2-yl)sulfonyl)piperidin-4-yl)cycloheptylurea;
N-(3-amidinophenyl)-Nxe2x80x2-(1-(6-carbomethoxyphenylsulfonyl)piperidin-4-yl)cycloheptylurea;
N-(3-amidinophenyl)-Nxe2x80x2-(2-pyridylmethyl)piperidin-4-yl)cycloheptylurea;
N-(3-amidinophenyl)-Nxe2x80x2-(3-pyridylmethyl)piperidin-4-yl)cycloheptylurea;
N-(3-amidinophenyl)-Nxe2x80x2-(4-pyridylmethyl)piperidin-4-yl)cycloheptylurea;
N-(3-amidinophenyl)-Nxe2x80x2-(phenyl-Nxe2x80x3-methylsulfamido)piperidin-4-yl)cycloheptylurea;
N-(3-amidinophenyl)-Nxe2x80x2-((4-phenylsulfonylthiophen-2-yl)sulfonyl)-piperidin-4-yl)cycloheptylurea;
N-(3-amidinophenyl)-Nxe2x80x2-(4-pyridylmethylsulfonyl)piperidin-4-yl)cycloheptylurea;
N-(3-amidinophenyl)-Nxe2x80x2-(thiophen-2-ylsulfonyl)piperidin-4-yl)cycloheptylurea;
N-(3-amidinophenyl)-Nxe2x80x2-(4-fluorobenzylsulfonyl)piperidin-4-yl)cycloheptylurea;
N-(3-amidinophenyl)-Nxe2x80x2-(2-pyridylsulfonyl)piperidin-4-yl)cycloheptylurea;
N-(3-amidinophenyl)-Nxe2x80x2-(2-trifluormethyl-phenylsulfonyl)piperidin-4-yl)cycloheptylurea;
N-(3-amidinophenyl)-Nxe2x80x2-(2-phenylisopropylsulfonyl)piperidin-4-yl)cycloheptylurea;
N-(3-amidinophenyl)-Nxe2x80x2-((1-((phenyl)-1,1-dimethyl)methane)sulfonyl)-piperidin-4-yl)cycloheptylurea;
N-(3-amidinophenyl)-Nxe2x80x2-(methyl((phenyl-methane)carbamide)morpholin-3-yl))cycloheptylurea;
N-(3-amidinophenyl)-Nxe2x80x2-(methyl((thiophen-2-yl)sulfonyl)morpholin-3-yl))cycloheptylurea;
N-(3-amidinophenyl)-Nxe2x80x2-(methyl((phenyl-methane)sulfonyl)morpholin-3-yl))cycloheptylurea;
N-(3-amidinophenyl)-Nxe2x80x2-((N-benzyl)piperidin-3-yl)cycloheptylurea;
N-(3-amidinophenyl)-Nxe2x80x2-((N-(benzyl)sulfonyl)-piperidin-3-yl)cycloheptylurea;
N-(3-amidinophenyl)-Nxe2x80x2-((N-(thiophen-2-yl)sulfonyl)piperidin-3-yl)cycloheptylurea;
N-(3-amidinophenyl)-Nxe2x80x2-(4-(2-sulfonamido-phenyl)phenyl)cycloheptylurea;
N-(3-amidinophenyl)-Nxe2x80x2-(5-(2-sulfonamido-phenyl)pyridin-2-yl)cycloheptylurea; and,
N-(3-amidinophenyl)-Nxe2x80x2-(methyl(4-(2-sulfonamidophenyl)phenyl))cycloheptylurea;
xe2x80x83or stereoisomers or pharmaceutically acceptable salt forms thereof.
[8] In another preferred embodiment, the present invention provides compounds wherein:
n is 2; and,
R2 and R21 are on adjacent carbon atoms and combine to form a benzene ring substituted with 0-2 R10 or a 5-6 membered aromatic heterocycle containing 0-2 heteratoms selected from the group consisting of N, O, and S and substituted with 0-2 R10a.
[9] In another more preferred embodiment, the present invention provides novel compounds of formula II: 
xe2x80x83or stereoisomers or pharmaceutically acceptable salt forms thereof, wherein;
ring N contains 0-2 N atoms and is substituted with 0-2 R10; and,
D is selected from CN, C(xe2x95x90NR11)NR12R13, NHC(xe2x95x90NR11)NR12R13, NR12CH(xe2x95x90NR11), C(O)NR12R13, and (CH2)tNR12R13.
[10] In another even more preferred embodiment, the present invention provides compounds of formula II wherein:
D is C(xe2x95x90NH)NH2;
R1 is selected from H, (CH2)rOR3, halo, (CH2)rNR4R4xe2x80x2, (CH2)rCO2H, (CH2)rC(xe2x95x90O)R4, (CH2)rNR4C(xe2x95x90O)R4, (CH2)rSO2R5, and (CH2)rNHSO2R5;
R4 and R4xe2x80x2 are independently selected from H, OR3, C1-4 alkyl, and NR3R3xe2x80x2;
R5 is selected from C1-4 alkyl and NR3R3xe2x80x2;
Z is selected from a bond, C1-4 alkylene, (CH2)rC(O)(CH2)r, (CH2)rC(O)NR3(CH2)r, (CH2)2NR3C(O)(CH2)r, (CH2)2OC(O)NR3(CH2)r, (CH2)2NR3C(O)O(CH2)r, (CH2)2NR3C(O)NR3(CH2)r, (CH2)rS(O)p(CH2)r, and (CH2)rSO2NR3(CH2)r; and,
X is selected from C1-4 alkylene, xe2x80x94CO(O), xe2x80x94C(O) CR3R3xe2x80x2xe2x80x94, xe2x80x94CR3R3xe2x80x2C(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94C(O)OCR3R3xe2x80x2, xe2x80x94CR3R3xe2x80x2C(O)Oxe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94OC(O)CR3R3xe2x80x2xe2x80x94, xe2x80x94CR3R3xe2x80x2OC(O)xe2x80x94, xe2x80x94S(O)pxe2x80x94, xe2x80x94S(O)pCR3R3xe2x80x2xe2x80x94, xe2x80x94CR3R3xe2x80x2S(O)pxe2x80x94, xe2x80x94C(O)NR3xe2x80x94, xe2x80x94NR3C(O)xe2x80x94, xe2x80x94NR3C(O)Oxe2x80x94, xe2x80x94OC(O)NR3xe2x80x94, xe2x80x94NR3C(O)NR3xe2x80x94, xe2x80x94NR3xe2x80x94, xe2x80x94NR3CR3R3xe2x80x2xe2x80x94, xe2x80x94CR3R3xe2x80x2NR3xe2x80x94, O, xe2x80x94CR3R3xe2x80x2Oxe2x80x94, and xe2x80x94OCR3R3xe2x80x2xe2x80x94.
[11] In another further preferred embodiment, the present invention provides compounds of formula II, wherein:
Z is selected from a bond, C1-4 alkylene, C(O)NR3(CH2)r, S(O)2, S(O)2CH2, and (CH2)rSO2NR3(CH2)r;
A is selected from phenyl substituted with 0-1 R6 and 6 membered heterocyclic system containing 1 N and substituted with 0-1 R6; and,
X is selected from C1-4 alkylene, xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)CR3R3xe2x80x2xe2x80x94, xe2x80x94CR3R3xe2x80x2C(O)xe2x80x94, xe2x80x94S(O)pxe2x80x94, xe2x80x94S(O)pCR3R3xe2x80x2xe2x80x94, xe2x80x94C(O)NR3xe2x80x94, and, xe2x80x94NR3xe2x80x94.
[12] In another even further preferred embodiment, the present invention provides compounds selected from:
1,2,4,5-tetrahydro-2-((phenyl)methane)-sulfonyl)piperidin-4-yl)-4-(3-amidinophenyl)-3H-2,4-benzodiazepin-3-one;
1,2,4,5-tetrahydro-2-(thiopen-2-yl)-sulfonyl)piperidin-4-yl)-4-(3-amidinophenyl)-3H-2,4-benzodiazepin-3-one;
1,2,4,5-tetrahydro-2-((phenyl)methane)-sulfonyl)piperidin-4-yl)-4-(3-amidinophenyl)-7,8-dimethoxy-3H-2,4-benzodiazepin-3-one; and,
1,2,4,5-tetrahydro-2-(thiophen-2-yl)-sulfonyl)piperidin-4-yl)-4-(3-amidinophenyl)-7,8-dimethoxy-3H-2,4-benzodiazepin-3-one.
In a second embodiment, the present invention provides novel pharmaceutical compositions, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or prodrug form thereof.
In a third embodiment, the present invention provides a novel method for treating or preventing a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or prodrug form thereof.
The compounds herein described may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Many geometric isomers of olefins, Cxe2x95x90N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated.
The term xe2x80x9csubstituted,xe2x80x9d as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom""s normal valency is not exceeded, and that the substitution results in a stable compound. When a substitent is keto (i.e., xe2x95x90O), then 2 hydrogens on the atom are replaced.
When any variable (e.g., R6) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R6, then said group may optionally be substituted with up to two R6 groups and R6 at each occurrence is selected independently from the definition of R6. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
As used herein, xe2x80x9cC1-6 alkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, examples of which include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, and hexyl; xe2x80x9cAlkenylxe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl, and the like.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d as used herein refers to fluoro, chloro, bromo, and iodo; and xe2x80x9ccounterionxe2x80x9d is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate, and the like.
As used herein, xe2x80x9ccarbocyclexe2x80x9d or xe2x80x9ccarbocyclic residuexe2x80x9d is intended to mean any stable 3- to 7-membered monocyclic or bicyclic or 7- to 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl,; [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).
As used herein, the term xe2x80x9cheterocyclexe2x80x9d or xe2x80x9cheterocyclic systemxe2x80x9d is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. As used herein, the term xe2x80x9caromatic heterocyclic systemxe2x80x9d is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and from 1 to 4 heterotams independently selected from the group consisting of N, O and S. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1.
Examples of heterocycles include, but are not limited to, 1H-indazole, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, benzothiadiazolyl, carbazolyl, 4aH-carbazolyl, xcex2-carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, xanthenyl. Preferred heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, or isatinoyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
The phrase xe2x80x9cpharmaceutically acceptablexe2x80x9d is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As used herein, xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington""s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
xe2x80x9cProdrugsxe2x80x9d are intended to include any covalently bonded carriers which release the active parent drug according to formula (I) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of formula (I) are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of formula (I) wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug or compound of formula (I) is administered to a mammalian subject, cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of formula (I), and the like. Preferred prodrugs are amidine prodrugs wherein D is C(xe2x95x90NR11)NH2, and R11 is selected from OH, C1-4 alkoxy, C6-10 aryloxy, C1-4 alkoxycarbonyl, C6-10 aryloxycarbonyl, C6-10 arylmethylcarbonyl, C1-4 alkylcarbonyloxy C1-4 alkoxycarbonyl, and C6-10 arylcarbonyloxy C1-4 alkoxycarbonyl. More preferred prodrugs are where R11 is OH, methoxy, ethoxy, benzyloxycarbonyl, methoxycarbonyl, and methylcarbonyloxymethoxycarbonyl.
xe2x80x9cStable compoundxe2x80x9d and xe2x80x9cstable structurexe2x80x9d are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
Compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include but are not limited to those methods described below. Each of the references cited below are hereby incorporated herein by reference. All the temperatures are reported herein in degrees Celsius.
The compounds of Formula 1 can be prepared using the reactions and techniques described below. The reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformations being effected. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule should be consistent with the transformations proposed. This will sometimes require a judgment to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention. It will also be recognized that another major consideration in the planning of any synthetic route in this field is the judicious choice of the protecting group used for protection of the reactive functional groups present in the compounds described in this invention. An authoritative account describing the many alternatives to the trained practitioner is Greene and Wuts (Protective Groups In Organic Synthesis, Wiley and Sons, 1991).
Two general approaches can be used for the preparation of the cyclic ureas of this invention. The first involves bimolecular cyclizations to the cyclic urea, as outlined in Scheme I, the second uses the internal unimolecular cyclizations of Scheme II. 
Route A of Scheme I illustrates the bis-alkylation of an N,Nxe2x80x2-disubstituted urea with an alkane substituted at both termini with an appropriate leaving group (L.G.), such as a halogen or sulfonate ester. The flexibility of this approach also allows for the bis-alkylation with an alkene or R2-substituted alkane which is again substituted at both termini with an appropriate leaving group (L.G.). Such alkylation agents are either commercially available, e.g. 1,4-dibromobutane and its lower homologs, found in the literature, e.g. the isopropylidene ether of 1,4-diiodido-2,3-dihydroxybutane (Deluca and Magnus, J. Chem. Soc. (Perkin Trans. I), 2661(1991), and Hoye and Suhadolnik, Tetrahedron, 42 (11) 2855 (1986)), or can be prepared by a practitioner skilled in the art using standard chemical methods.
The N,Nxe2x80x2-disubstituted urea can be generated from two primary amines, one of which must be a Q,R1-substituted aniline wherein Q is a functional group from which an amidine could be readily generated such as nitrile; in some special cases Q may be tolerated as a mono- or di- acyl or carbamoyl protected amidine. The second primary amine, H2Nxe2x80x94Zxe2x80x94Axe2x80x94B, may be any amine deemed appropriate within the limits of Formula 1. This amine may be commercially available, e.g. 1-benzyl-4-aminopiperidine, found in the literature, e.g. 1-t-butoxycabonyl-4-aminopiperidine (Mach et al., J. Med. Chem., 36(23), 3707 (1993)), or can be prepared by a practitioner skilled in the art utilizing standard chemical methods.
The two primary amines described above can be assembled to the desired N,Nxe2x80x2-disubstituted urea by selecting one for transformation to the corresponding isocyanate in situ by stirring with phosgene or its equivalent such as trichloromethyl chloroformate or p-nitrophenylchloroformate in the presence of a trialkylamine base and a dry, aprotic solvent such as dimethylformamide, dioxane, benzene or a chlorinated alkane. The temperature of this reaction may be varied from xe2x88x9210xc2x0 C. to the reflux point of the solvent (Takeda et al., Tetrahedron Lett., 24(42) 4569 (1983), Cortez et al., Synth. Commun., 21(2) 285 (1991)). Alternatively the desired isocyanate may be commercially available, such as 3-cyanophenyl isocyanate, in which case convenience dictates that this substrate be used. Conditions for direct reaction of a preformed isocyanate are similar to those described above with the caveat that the phosgene equivalent is necessary, and the trialkylamine base may be omitted (Shiau et al., J. Heterocyclic Chem., 26, 595(1989)).
Ring formation in Route A is achieved by alkylation of the N,Nxe2x80x2-disubstituted urea with the dihalogenated (Curtis, Aust. J. Chem., 41 585 (1988), Htay et al., Tetrahedron Lett., 79 (1976), Sulsky et al., Synth. Commun., 19, 1871 (1989)) or disulfonated (Ayyana et al., Chem. Ind. (London), 599 (1988)) alkylating agent described above. Typically, the disubstituted urea is added at ambient temperature or lower to a mixture of at least two equivalents of strong base such as sodium hydride, potassium t-butoxide or an alkyl lithium in an appropriate anhydrous solvent such as tetrahydrofuran, dimethylformamide, t-butanol, toluene or dimethylsulfoxide. After deprotonation is complete, a solution of the alkylating agent in the selected solvent is added slowly to the disubstituted urea at ambient temperature or lower; when the addition is completed, the reaction may be continued at ambient temperature or lower or heated up to the reflux temperature of the solvent, depending upon the reactivity of the alkylating agent/disubstituted urea pair and the patience of the practitioner.
Route B of Scheme I illustrates use of an appropriately substituted diamine and phosgene or its equivalent to generate a cyclic urea precursor to Formula 1. The required diamine can be generated by two approaches. The first approach utilizes a Q,R1-substituted aniline which is conjoined with an N-acyl or N-carbamoyl protected secondary amine where G is a halogen or sulfonate ester leaving group for a standard alkylation of the Q,R1-substituted aniline or G could be an aldehyde suitable for reductive alkylation of the Q,R1-substituted aniline. The second approach to diamine formation conjoins an N-acyl or N-carbamoyl protected N-alkylated Q,R1-substituted aniline, where G is as described above, with primary amine H2Nxe2x80x94Zxe2x80x94Axe2x80x94B by a standard or reductive alkylation.
Both protected secondary amines are available by similar chemistry. The selected aniline or primary amine H2Nxe2x80x94Zxe2x80x94Axe2x80x94B is protected with a N-acyl or N-carbamoyl protecting group according to a method specified in Greene and Wuts; N-t-butoxy carbamoyl is useful for this application. This protected amine can then be cleanly mono-alkylated with one of the dihalogenated or disulfonylated alkylating agents recommended for Route A (Reed et al., Tetrahedron Lett., 79(45) 5725 (1988)). Alternatively, the protected amine can be mono-alkylated with a protected halo alcohol. Both alkylations are readily achieved in anhydrous aprotic solvents such as toluene, tetrahydrofuran, dimethylformamide or dimethylsulfoxide at temperatures ranging from xe2x88x9278xc2x0 C. to the reflux temperature of the selected solvent with a strong base such as sodium hydride, potassium t-butoxide or an alkyl lithium. In the case where G is a protected alcohol, the protecting group is removed and an aldehyde generated by Moffatt oxidation (Pfitzner and Moffatt, J. Amer. Chem. Soc., 87 5661 (1965)) or through use of pyridinium chlorochromate (Corey and Suggs, Tetrahedron Lett., 2647 (1975)) or pyridinium dichromate in dichloromethane (Coates and Corrigan, Chem. Ind. (London), 1594 (1969)).
The required diamine can then be prepared by stirring the alkylating agent with the primary amine component either neat or in an aprotic solvent such as toluene, tetrahydrofuran, dimethylformamide or dimethylsulfoxide. The temperature of this reaction may range from xe2x88x9278xc2x0 C. to the reflux temperature of the selected solvent. A strong base such as sodium hydride, potassium t-butoxide or an alkyl lithium or a weaker trialkylamine base may be used, depending upon the reactivity of the two components. As an alternative, when G is an aldehyde, a reductive alkylation of the primary amine component is possible. The direct method involves the use of a borohydride reducing agent, most preferably sodium or lithium cyanoborohydride, in a mixture of aldehyde and amine components in an alcoholic solvent (Borch et al., J. Amer. Chem. Soc., 93 2897 (1971)). A stepwise method involves generation of an intermediate imine/enamine by azeotropic removal of water from a heated mixture of aldehyde and primary amine component in a suitable solvent such as benzene at reflux temperature. The imine/enamine intermediate can then be isolated and reduced by palladium catalyst under an atmosphere of hydrogen gas at ambient pressure or higher or reduced by borohydride reagents under conditions similar to those preferred for the direct method. The required diamine is generated by removal of the protecting group according to a method recommended in Greene and Wuts.
The diamine formed above is reacted with phosgene or its equivalent such as trichloromethyl chloroformate or p-nitrophenylchloroformate in the presence of an excess of a trialkylamine base and a dry, aprotic solvent such as dimethylformamide, dioxane, toluene, benzene or a chlorinated alkane to form a cyclic urea precursor to Formula 1. The temperature of this reaction may be varied from xe2x88x9210xc2x0 C. to the reflux point of the solvent. 
Two alternatives, Route C and Route D, for the preparation of precursors of Formula 1 by a unimolecular cyclization method are outlined in Scheme II. In Route C one begins by alkylating a Q,R1-substituted aniline with a halogenated alkylalcohol, such as 4-bromobutan-1-ol or its homologs, or a protected version of the same, such as the methoxymethyl ether of 4-bromobutan-1-ol, either neat or in an anhydrous solvent such as dimethylformamide, benzene, tetrahydrofuran, hexamethylphosphorotriamide, or dimethylsulfoxide. This reaction may be furthered by heating the mixture up to the reflux point of the solvent. Depending upon the reactivity of the substrate no base, or a strong base, such as sodium hydride, potassium t-butoxide or an alkyl lithium, or a weak base, such as potassium carbonate or a trialkylamine, may be necessary. The alkylation product is then reacted with an isocyanate OCNxe2x80x94Zxe2x80x94Axe2x80x94B generated from the amine NH2xe2x80x94Zxe2x80x94Axe2x80x94B by the same method described above for Route A of Scheme I to give a product alcohol or protected alcohol which can be transformed to a halogenated or sulfonyl ester analog for cyclization to a cyclic urea precursor to Formula 1.
Following deprotection according to an appropriate method found in Greene and Wuts (if necessary), halogenation of the primary alcohol can be carried out with a variety of reagents such as neat thionyl chloride, triphenylphosphine in carbon tetrachloride (Lee and Downie, Tetrahedron, 23 359 (1967)), or triphenylphosphine with N-chloro- or N-bromosuccinimide in dimethylformamide. The alternative sulfonyl ester is also readily prepared from an appropriate sulfonyl chloride, such as the commercially available p-toluenesulfonyl chloride or methanesulfonyl chloride, in a variety of anhydrous aprotic solvents, such as pyridine, benzene, tetrahydrofuran or a chlorinated hydrocarbon, with or without cooling, and with or without a trialkylamine base.
Ring closure to a cyclic urea precursor to Formula 1 has been observed to occur spontaneously in some cases, but may be furthered in an anhydrous solvent such as dimethylformamide, benzene, tetrahydrofuran, hexamethylphosphorotriamide, or dimethylsulfoxide, by heating the mixture up to the reflux point of the solvent. Depending upon the reactivity of the substrate no base, or a strong base, such as sodium hydride, potassium t-butoxide or an alkyl lithium, or a weak base, such as potassium carbonate or a trialkylamine, may be necessary.
Route D of Scheme II may be advantageous over Route C for the availability of starting materials such as the commercially produced 1-benzyl-4-aminopiperidine for NH2xe2x80x94Zxe2x80x94Axe2x80x94B component, 2-bromoethanol for the halo alcohol component, and 3-cyanophenyl isocyanate for the isocyanate component. In any respect, the chemistry described in Route C is applicable to an analogous reaction in Route D with modifications appropriate for the particular materials involved.
In Formula 1 the radical Z serves as a linking group interposed between the cyclic urea structure and radical Axe2x80x94B. For the purposes of this discussion it is recognized that there are variations of Z, that is where Z=a bond or C1-4 alkylene or a portion of the defined linkage, that for synthetic purposes are best incorporated as a substituent of A. It is also assumed for the purpose of this discussion that the analog of A used throughout may contain an orthogonal protecting group, which is compatible with the chemistry suggested. Furthermore, this protecting group may be removed to reveal a substituent that can be used to generate a group X. 
The preparation of Z outlined in Scheme III begins with the 0-protected derivative of 2-aminoethanol. The t-butyldimethylsilyl analog is recommended for this purpose and is know in the literature (see WO 9504277 and WO 9205186). However, a worker skilled in the art would recognize that the approaches discussed herein are not limited to this particular analog of 2-aminoethanol. O-Protected 2-aminoethanol can then be protected as the N-t-butoxycarbonyl analog and selectively O-deprotected according to procedures found in Greene and Wuts. The resulting 2xe2x80x94(N-t-butoxycarbamoyl)ethanol (1) can then be reacted with various analogs of A to give the desired group Z.
Product 2 is the result of reaction of the chlorocarbonate analog of A with 1 in a variety of aprotic solvents, such as a chlorocarbon, tetrahydrofuran, or pyridine, with or without a trialkylamine base at temperatures ranging from xe2x88x9278xc2x0 to ambient temperature. The carbonyl chloride analog of A (A(CH2)rOC(O)Cl) is avaialable by reaction of an appropriate alcohol analog of A with phosgene or one of its equivilents in a variety of aprotic solvents, such as a chlorocarbon, tetrahydrofuran, or pyridine, with or without a trialkylamine base at temperatures ranging from xe2x88x9278xc2x0 to ambient temperature.
Product 3 is prepared by reaction of the acid chloride of an appropriate acid analog of A with 1 in a variety of aprotic solvents, such as a chlorocarbon, tetrahydrofuran, or pyridine, with or without a trialkylamine base at temperatures ranging from xe2x88x9278xc2x0 to ambient temperature. The acid chloride can be obtained by reaction of the acid analog of A with phosphorous oxychloride, phosphorous pentachloride, thionyl chloride or oxalyl chloride with or without a non-polar aprotic solvent such as a chlorocarbon, benzene or toluene at temperatures ranging from 0xc2x0 C. to the reflux point of the solvent or neat reagent.
Product 4 can be prepared by the reaction of a carbamoyl chloride analog of A with 1 in a variety of aprotic solvents, such as a chlorocarbon, tetrahydrofuran, or pyridine, with or without a trialkylamine base at temperatures ranging from xe2x88x9278xc2x0 C. to ambient temperature. The carbamoyl chloride analog of A (A(CH2)rNR3C(O)Cl) is avaialable by reaction of an appropriate amine analog of A with phosgene or one of its equivilents in a variety of aprotic solvents, such as a chlorocarbon, tetrahydrofuran, or pyridine, with or without a trialkylamine base at temperatures ranging from xe2x88x9278xc2x0 C. to ambient temperature.
Product 5 is available by the reaction of an analog of A substituted with an appropriate leaving group with the alkoxide generated from 2 by treatment of 2 with a strong base such as sodium or potassium hydride or a thallium alkoxide in an aprotic solvent such as dimethylformamide, tetrahydrofuran or dimethylsulfoxide at a temperature ranging from 0 to 120xc2x0 C. The leaving group of A is most conviently generated from an appropriate alcohol analog of A. The alcohol function can be used to prepare a sulfonate ester from a sulfonyl chloride in a cholorocarbon solvent with a trialkylamine base or in pyridine; alternatively the halogen can be generated from a variety of reagents, triphenyl phosphine and carbon tetrabromide, phosphorous pentabromide or chloride, and thionyl chloride, to name a few. 
The series of analogs in Scheme IV can be prepared from the protected amino alcohol 6 to give products 7 to 12 by methods similar to some of those described for Scheme III. Compound 6 is prepared from 2-amino-(O-t-butyldimethyl-silyl)ethanol by reductive amination of the primary amine by a variety of methods. The primary amine may be reacted with an aldehyde or ketone under dehydrating conditions to form an imine or enamine intermediate which is then reduced to the N-alkyl derivative using palladium catalyst under an atmosphere of hydrogen in an appropriate solvent. Alternatively, reductive alkylation can be effected by a mixture of the ketone or aldehyde and the amine with lithium or sodium cyanoborohydride in methanol or ethanol as solvent.
It is to be understood that products 7 to 12 need to have the terminal protected oxygen transformed to the primary amine either at this stage or after elaboration with group B. This can conveniently be achieved by deprotection of the primary alcohol. The alcohol function can then be used to prepare a sulfonate ester from a sulfonyl chloride in a chlorocarbon solvent with a trialkylamine base or in pyridine; alternatively a halogen can be generated from a variety of reagents, triphenyl phosphine and carbon tetrabromide, phosphorous pentabromide or chloride, and thionyl chloride, to name a few. The resulting leaving group is then displaced with a mixture of sodium azide in dimethylformamide at an elevated temperature to form the primary azide. The azide can then be reduced to the amine by catalytic hydrogenation in an alcoholic solvent with palladium catalyst under an atmosphere of hydrogen gas at pressures ranging from ambient to 65 psi; an alternative method for effecting this transformation involves refluxing the azide intermediate with triphenylphosphine in benzene or toluene and hydrolyzing the resulting intermediate with aqueous acid.
Product 7 of Scheme IV is the result of the reaction of the chlorocarbonate analog of A with 6 in a variety of aprotic solvents, such as a chlorocarbon, tetrahydrofuran, or pyridine, with or without a trialkylamine base at temperatures ranging from xe2x88x9278xc2x0 C. to ambient temperature. Product 8 is prepared by the reaction of the acid chloride of an appropriate acid analog of A with 6 in a variety of aprotic solvents, such as a chlorocarbon, tetrahydrofuran, or pyridine, with or without a trialkylamine base at temperatures ranging from xe2x88x9278xc2x0 C. to ambient temperature. Product 9 can be prepared by the reaction of a carbamoyl chloride analog of A with 6 in a variety of aprotic solvents, such as a chlorocarbon, tetrahydrofuran, or pyridine, with or without a trialkylamine base at temperatures ranging from xe2x88x9278xc2x0 to ambient temperature.
Product 10 may be obtained from 7 by two routes, conventional alkylation or reductive alkylation. If 6 is a primary amine, then reductive alkylation is recommended. The primary amine 6 may be reacted with an aldehyde or ketone analog of A under dehydrating conditions to form an imine or enamine intermediate which is then reduced to the N-alkyl derivative using palladium catalyst under an atmosphere of hydrogen in an appropriate solvent. Alternatively, reductive alkylation can be effected by a mixture of the ketone or aldehyde and the amine with lithium or sodium cyanoborohydride in methanol or ethanol as solvent. The aldehyde or ketone analog of A is readily accessible from the appropriate alcohol by Swern, Moffat or Jones oxidation. In the case where 6 is a secondary amine product 10 is available by the reaction of an analog of A substituted with an appropriate leaving group with 7 in the presence of a weak base such as a trialkylamine or solid sodium or potassium carbonate in an aprotic solvent such as dimethylformamide, acetone, tetrahydrofuran or dimethylsulfoxide at a temperature ranging from 0xc2x0 to 120xc2x0 C.
Product 11 is prepared by the reaction of the sulfonyl chloride of an appropriate analog of A with 6 in a variety of aprotic solvents, such as a chlorocarbon, tetrahydrofuran, or pyridine, with or without a trialkylamine base at temperatures ranging from xe2x88x9278xc2x0 to ambient temperature. The sulfonyl chloride analog of A is available via the sulfonic acid of A which can be prepared by heating a halogen analog of A in a aqueous sodium sulfite. The sulfonyl chloride of A can be prepared by reacting the sulfonic acid with phosphorous oxychloride, phosphorous pentachloride, thionyl chloride or oxalyl chloride with or without a non-polar aprotic solvent such as a chlorocarbon, benzene or toluene at temperatures ranging from 0xc2x0 C. to the reflux point of the solvent or neat reagent. Product 12 is prepared by the reaction of the sulfamoyl chloride of an appropriate analog of A with 6 in a variety of aprotic solvents, such as a chlorocarbon, tetrahydrofuran, or pyridine, with or without a trialkylamine base at temperatures ranging from xe2x88x9278xc2x0 C. to ambient temperature. 
Scheme V outlines the preparation of variations of Z that are not readily prepared by the strategies in Schemes III and IV. Compound 13 is available by the routes developed 20 in Schemes I and II by replacing the primary amine NH2ZAB with O-t-butyldimethylsilyl-2-aminoethanol or its propanol homolog. Jones oxidation of 13 gives corresponding carboxylic acid which is then transformed to the acid chloride 14 by one of the methods outlined in the preceding discussion. The ester 15 is prepared by reaction of 14 with an alcohol derivative of A under conditions similar to those detailed for the preparation of ester 2 in Scheme III. The amide 16 is available by the reaction of 14 with an amine derived from A under conditions similar to those used for the formation of amide 8 found in Scheme IV. The sulfonyl chloride 17 of Scheme V is prepared by the alcohol to halide to sulfonic acid to sulfonyl chloride route discussed for the sulfonyl analogs of Scheme IV. Reaction of 17 with an amine derivative of A under conditions used for the formation of 11 in Scheme IV gives the sulfonamide 18 of Scheme V. 
In Scheme VI two approaches to the incorporation of group B are outlined; in each case it is assumed that the starting structures are suitably protected to accommodate the chemistry that follows. It is also understood that both approaches may not be equivilent and, for purposes of compatibility with the chemistry that follows, one approach may have certain advantages over the other. It is further assumed that groups A and B have been selected to be derivatives of A and B that contain functionality suitable for the chemistry contemplated. Groups A and B are available either through commercial sources, known in the literature or readily synthesized by the adaptation of standard procedures known to practioners skilled in the art of organic synthesis.
The required reactive functional groups appended to analogs of A and B are also available either through commercial sources, known in the literature or readily synthesized by the adaptation of standard procedures known to practioners skilled in the art of organic synthesis. In the tables that follow the chemistry required to effect the coupling of A to B is outlined.
The chemistry of Table 1 can be carried out in aprotic solvents such as a chlorocarbon, pyridine, benzene or toluene, at temperatures ranging from xe2x88x9220xc2x0 C. to the reflux point of the solvent and with or without a trialkylamine base.
The coupling chemistry of Table 2 can be carried out by a variety of methods. The Grignard reagent required for Y is prepared from a halogen analog of Y in dry ether, dimethoxyethane or tetrahydrofuran at 0xc2x0 C. to the reflux point of the solvent. This Grignard reagent can be reacted directly under very controlled conditions, that is low temeprature (xe2x88x9220xc2x0 C. or lower) and with a large excess of acid chloride or with catalytic or stoichiometric copper bromideedimethyl sulfide complex in dimethyl sulfide as a solvent or with a varient thereof. Other methods available include transforming the Grignard reagent to the cadmium reagent and coupling according to the procedure of Carson and Prout (Org. Syn. Col. Vol. 3 (1955) 601) or a coupling mediated by Fe(acac)3 according to Fiandanese et al. (Tetrahedron Lett., (1984) 4805), or a coupling mediated by manganese (II) catalysis (Cahiez and Laboue, Tetrahedron Lett., 33(31), (1992) 4437).
The ether and thioether linkages of Table 3 can be prepared by reacting the two components in a polar aprotic solvent such as acetone, dimethylformamide or dimethylsulfoxide in the presence of a base such as potassium carbonate, sodium hydride or potassium t-butoxide at temperature ranging from ambient temperature to the reflux point of the solvent used.
The thioethers of Table 3 serve as a convenient starting material for the preparation of the sulfoxide and sulfone analogs of Table 4. A combination of wet alumina and oxone provides a reliable reagent for the oxidation of the thioether to the sulfoxide while m-chloroperbenzoic acid oxidation will give the sulfone. 
A cyclic urea precursor of Formula 1 which is suitable for the preparation of analogs where Z=xe2x80x94C(O)xe2x80x94 or xe2x80x94SO2xe2x80x94 can be synthesized by an adaptation of the chemistry outlined in Scheme I. The approach in Scheme VII makes use of a N-hydrazino-alkylbromide as the alkylating agent for the aniline derivative. The alkylation product is then deprotected according to a method proscribed by Greene and Wutts and cyclized by treatment of the resulting diamine with phosgene or one of its equivilents. The resulting cyclic urea can be treated with a strong base such as sodium hydride or potassium t-butoxide in an aprotic solvent like dimethyl formamide, dimethylsulfoxide or toluene. This mixture is quenched with an acid chloride or sulfonyl chloride analog of Axe2x80x94B at a temperature ranging from xe2x88x9278xc2x0 C. to the reflux point of the solvent. 
The final transformation of the cyclic urea precursor of Formula 1 prepared in Schemes I to VII to Formula 1 is outlined in Scheme VIII. The preferred method was first described by Pinner and Klein (Ber., 10, 1889 (1877); for a more recent review see: Decroix, J. Chem. Res., 134 (1978)). By this method the nitrile is dissolved in an anhydrous alcohol or a mixture of 1 equivalent or greater of an alcohol and an anhydrous aprotic co-solvent such as a chlorohydrocarbon or an acetate ester of the selected alcohol (i.e., methyl acetate for methyl alcohol). Typically, this mixture is cooled below ambient temperature and dry hydrogen chloride gas is added slowly to the reaction mixture until the solvent is saturated. This saturated solution is sealed and stirred at ambient temperature or lower to form an imidate intermediate which is isolated and characterized. The imidate is then dissolved in a dry alcohol solvent and excess ammonia in the form of a gas, a standardized ammonia/alcohol solution, solid ammonium acetate or ammonium carbonate is added. The crude compound is conveniently purified by reverse phase HPLC or recrystallization to give the cyclic urea defined by Formula 1.
Scheme IX outlines the general route for the preparation of 5-membered aryl- or heteroaryl-fused examples of Formula II. The preparation of the biaryl amine intermediate can be accomplished by the palladium catalyzed coupling of the substituted aniline to the triflate ester according to the method of Louie et. al., (J. Org. Chem.1997, 62, 1268-1273). 
The aniline nitrogen can then be protected as a carbamate, the nitro group reduced to the amine. This amine can be coupled with a Zxe2x80x94Axe2x80x94B group in which Z incorporates a carbonyl group, such as an aldehyde, which can be used as a reactive partner in a reductive alkylation of the newly generated amine. The resulting intermediate can then be processed according to the art described for Route B of Scheme I. 
The steps which can be used for the regiocontrolled preparation of both isomers of the 6-membered aryl- or heteroaryl-fused examples of Formula II is outline in Routes A and B of Scheme X. One regioisomer is available by applying the chemistry developed by Louie et al. to the triflate of the salicylate ester in Route A. Following protection of the resulting biaryl amine, the ester can be reduced by lithium borohydride or some other compatible hydride reducing agent and then processed further as outline in Route B of Scheme I.
The alternative regioisomer of Formula II contemplated by this invention can be prepared according to Route B of Scheme X. To effect the palladium catalyzed coupling of the H2Nxe2x80x94Zxe2x80x94Axe2x80x94B group with the triflate salicylate ester the conditions reported by Wolfe and Buchwald (Pd(OAc)2, BiNAP, NaO-t-Bu, toluene; J. Org. Chem. 1997, 62, 1264-1267) are optimal. The amine coupling product is then suitably N-protected and the ester functionality is reduce to the benzylic alcohol. This intermediate is then treated further according to the methods outlined in Scheme I, Route B. 
Scheme XI describes the route used to prepare a precursor to one regioisomer of the 7-membered aryl- or heteroaryl-fused example of Formula II. The point of departure is usually the 2-cyano substituted aryl- or heteroaryl-ester. Lithium aluminum hydride reduction of these compounds leads to the corresponding amino alcohol which can then be selectively O-protected with a silyl protecting group, preferably the t-butyl dimethylsilyl group. This material is now ready for reductive alkylation by a Zxe2x80x94Axe2x80x94B group in which Zxe2x80x94 contains a carbonyl compound such as an aldehyde, ketone or cyclic ketone. In our experience this transformation can best be performed using a mixture of sodium cyanoborohydride and zinc chloride in tetrahydrofuran solvent. Following reductive alkylation the resulting secondary amine is reacted with an aryl isocyanate in an inert solvent such as dimethylformamide. The isocyanate addition product can then be O-deprotected, and the benzylic alcohol be transformed to the benzylic chloride with a mixture of methanesulfonyl chloride and triethylamine in chloroform or dichloromethane. The benzylic chloride is then cyclized to the 7-membered ring precursor to Formula II with sodium hydride in dimethylformamide at 0xc2x0 C. 
Routes to alternative regioisomers for 7-membered aryl- or heteroaryl-fused examples of Formula II are demonstrated in Scheme XII. In Route A, the phenethylnitro triflate can undergo a palladium catalyzed coupling with the aniline analog according to the procedure of Louie et al. The coupled product is then N-protected, usually as a carbamate or amide, then the nitro group is reduced to the amine by catalytic hydrogenation or with tin(II) chloride in aqueous or alcohol solvent. A Zxe2x80x94Axe2x80x94B group in which Zxe2x80x94 incorporates a carbonyl functionality can then be used as a partner in a reductive alkylation with the primary amine function under the conditions described previously. This intermediate can then be submitted to the chemistry described in Scheme I, Route B to obtain a compound of Formula II. Route B describes the coupling of a protected phenethyl alcohol triflate with an amine containing Zxe2x80x94Axe2x80x94B group under the conditions recommended by Wolfe and Buchwald. This product is then N-protected as a suitable carbamate or amide and then processed by the chemistry described in Route B of Scheme I.